The Eighth and Ninth Transmembrane Domains in Organic Anion Transporting Polypeptide 1B1 Affect the Transport Kinetics of Estrone-3-Sulfate and Estradiol-17β-D-glucuronide

2009 ◽  
Vol 329 (2) ◽  
pp. 551-557 ◽  
Author(s):  
Mayuko Miyagawa ◽  
Kazuya Maeda ◽  
Akinori Aoyama ◽  
Yuichi Sugiyama
Keyword(s):  
Organic Anion ◽  
Transmembrane Domains ◽  
Transport Kinetics ◽  
Organic Anion Transporting Polypeptide ◽  
Kinetics Of ◽  
Estradiol 17Β

pH-dependent transport kinetics of the human organic anion-transporting polypeptide 1A2

2020 ◽  
Vol 35 (2) ◽  
pp. 220-227 ◽  
Author(s):  
Tokio Morita ◽  
Takeshi Akiyoshi ◽  
Ryo Sato ◽  
Kazuhiro Katayama ◽  
Kodai Yajima ◽  
...  
Keyword(s):  
Organic Anion ◽  
Transport Kinetics ◽  
Organic Anion Transporting Polypeptide ◽  
Ph Dependent ◽  
Dependent Transport ◽  
Kinetics Of

scholarly journals The Blood-Brain Barrier Thyroxine Transporter Organic Anion-Transporting Polypeptide 1c1 Displays Atypical Transport Kinetics

Endocrinology ◽  
2009 ◽  
Vol 150 (11) ◽  
pp. 5153-5162 ◽  
Author(s):  
Daniel E. Westholm ◽  
David R. Salo ◽  
Kevin J. Viken ◽  
Jon N. Rumbley ◽  
Grant W. Anderson
Keyword(s):  
Binding Sites ◽  
Organic Anion ◽  
Transport Processes ◽  
Transport Kinetics ◽  
Brain Barrier ◽  
Hek293 Cells ◽  
Published Data ◽  
Organic Anion Transporting Polypeptide ◽  
Wide Range ◽  
Dependent Inhibition

Organic anion-transporting polypeptide (Oatp) 1c1 is a high-affinity T4 transporter expressed in brain barrier cells. Oatp1c1 transports a variety of additional ligands including the conjugated sterol estradiol 17β-glucuronide (E217βG). Intriguingly, published data suggest that E217βG inhibition of Oatp1c1-mediated T4 transport exhibits characteristics suggestive of atypical transport kinetics. To determine whether Oatp1c1 exhibits atypical transport kinetics, we first performed detailed T4 and E217βG uptake assays using Oatp1c1 stably transfected HEK293 cells and a wide range of T4 and E217βG concentrations (100 pm to 300 nm and 27 nm to 200 μm, respectively). Eadie-Hofstee plots derived from these detailed T4 and E217βG uptake experiments display a biphasic profile consistent with atypical transport kinetics. These data along with T4 and E217βG cis-inhibition dose-response measurements revealed shared high- and low-affinity Oatp1c1 binding sites for T4 and E217βG. T4 and E217βG recognized these Oatp1c1 binding sites with opposite preferences. In addition, sterols glucuronidated in the 17 or 21 position, exhibited preferential substrate-dependent inhibition of Oatp1c1 transport, inhibiting Oatp1c1-mediated E217βG transport more strongly than T4 transport. Together these data reveal that Oatp1c1-dependent substrate transport is a complex process involving substrate interaction with multiple binding sites and competition for binding with a variety of other substrates. A thorough understanding of atypical Oatp1c1 transport processes and substrate-dependent inhibition will allow better prediction of endo- and xenobiotic interactions with the Oatp transporter.

Liver and Statins: A Critical Appraisal of the Evidence

2019 ◽  
Vol 25 (42) ◽  
pp. 5835-5846 ◽  
Author(s):  
Anna Licata ◽  
Antonina Giammanco ◽  
Maria Giovanna Minissale ◽  
Salvatore Pagano ◽  
Salvatore Petta ◽  
...  
Keyword(s):  
Adverse Events ◽  
Association Studies ◽  
Organic Anion ◽  
Genome Wide Association Studies ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Organic Anion Transporting Polypeptide ◽  
Treatment And Prevention ◽  
Genome Wide ◽  
Underlying Mechanisms

Adverse drug reactions (ADRs) represent an important cause of morbidity and mortality worldwide. Statins are a class of drugs whose main adverse effects are drug-induced liver injury (DILI) and myopathy. Some of these may be predictable, due to their pharmacokinetic and pharmacodynamic properties, while others, unfortunately, are idiosyncratic. Genetic factors may also influence patient susceptibility to DILI and myopathy in the case of statins. This review will first discuss the role of statins in cardiovascular disease treatment and prevention and the underlying mechanisms of action. Furthermore, to explore the susceptibility of statin-induced adverse events such as myopathy and hepatotoxicity, it will then focus on the recent Genome-Wide Association Studies (GWAS) concerning the transporter genes, Cytochrome P450 (CYP), organic anion-transporting polypeptide (OATP) and ABCB1 and ABCC1, which seem to play a role in the development of clinically relevant adverse events. Finally, we appraise the evidence for and against the use of statins in metabolic syndrome and in HCV-infected patients, in terms of their safety and efficacy in cardiovascular events.

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